The present invention relates to triazole compounds and to the use of such compounds. The compounds mentioned have valuable therapeutic properties and can be used for treating diseases which respond to dopamine D3 receptor ligands.
Compounds of this type having physiological activity have been disclosed. U.S. Pat. Nos. 4,338,453; 4,408,049 and 4,577,020 describe triazole compounds which have antiallergic or antipsychotic activity. DE-A 44 25 144 and WO 97/25324 describe triazole compounds which respond to dopamine D3 receptor ligands. Compounds of the same structural type, however with other heterocycles in place of the triazole ring are disclosed in DE-A-44 25 146, DE-A-44 25 143 and DE 44 25 145.
Neurons obtain their information by way of G protein-coupled receptors, inter alia. A large number of substances exert their effect by way of these receptors. One of these substances is dopamine.
It is known with certainty that dopamine is present and that it has a physiological function as a neurotransmitter. Cells responding to dopamine are connected with the etiology of schizophrenia and Parkinson""s disease. These and other diseases are treated with drugs which interact with the dopamine receptors.
Prior to 1990, two dopamine receptor subtypes were clearly defined pharmacologically, ie. the D1 and D2 receptors.
More recently, a third subtype has been found, ie. the D3 receptor, which appears to mediate some of the effects of the antipsychotic drugs. (J. C. Schwartz et al., The Dopamine D3 Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H. Y. Meltzer, Ed. Raven Press, New York 1992, pages 135-144)
D3 receptors are principally expressed in the limbic system. It is therefore assumed that a selective D3 antagonist would probably have the antipsychotic properties of the D2 antagonists but would not have their neurological side effects. (P. Solokoff et al., Localization and Function of the D3 Dopamine Receptor, Arzneim. Forsch./Drug Res. 42(1), 224 (1992); P. Solokoff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D3) as a Target for Neuroleptics, Nature, 347, 146 (1990)).
Surprisingly, it has now been found that certain triazole compounds exhibit a high affinity for the dopamine D3 receptor and a low affinity for the D2 receptor. These compounds are therefore selective D3 ligands.
The present invention relates, therefore, to compounds of the formula I: 
where
Ar1 is phenyl, naphthyl or a 5- or 6-membered heterocyclic aromatic ring having from 1, 2, 3 or heteroatoms which are independently selected from O, S and N, where Ar1 may have 1, 2, 3 or 4 substituents which are selected, independently of each other, from C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl, halogen or phenyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, halogen, CN, COOR2, NR2R2, NO2, SO2R2, SO2NR2R2, or phenyl, which may be substituted by C1-C6-alkyl, OC1-C6-alkyl, NR2R2, CN, CF3, CHF2, or halogen, and where the heterocyclic, aromatic ring mentioned may be fused to a phenyl ring;
A is straight-chain or branched C4-C10-alkylene or straight-chain or branched C3-C10-alkylene which comprises at least one group Z which is selected from O, S, NR2, CONR2, COO, CO, or a double or triple bond,
B is a radical of the formula: 
or, if Ar1 represents the 5- or 6-membered, heterocyclic or aromatic ring which may be substituted as indicated, B may also be a radical of the formulae 
Ar2 is phenyl, pyridyl, pyrimidinyl or triazinyl, where Ar2 may have from 1 to 4 substituents which are selected, independently of each other, from OR2, C1-C6 alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cl-C6-alkoxy-Cl-C6-alkyl, halogen-C1-C6-alkyl, halogen-C1-C6-alkoxy, halogen, CN, NO2, SO2R2, NR2R2, SO2NR2R2, a 5- or 6-membered carbocyclic, aromatic or non-aromatic ring and a 5- or 6-membered, heterocyclic aromatic or non-aromatic ring having 1 or 2 heteroatoms which are selected from O, S and N, where the carbocyclic or heterocyclic ring may be substituted by Cl-C6-alkyl, phenyl, phenoxy, halogen, OC1-C6-alkyl, OH, NO2 or CF3 and where Ar2 may be fused to a carbocyclic or heterocyclic ring of the above-defined nature,
R1 is H, C3-C6-cycloalkyl or C1-C6-alkyl which may be substituted by OH, OC1-C6-alkyl or phenyl;
the radicals R2, which can be identical or different, are H or C1-C6-alkyl, which may be substituted by OH, OC1-C6-alkyl or phenyl;
and their salts with physiologically tolerated acids.
The novel compounds are selective dopamine D3 receptor ligands which act in a regioselective manner in a limbic system and which, due to their low affinity for the D2 receptor, have fewer side effects than the classic neuroleptics, which are D2 receptor antagonists. The compounds can therefore be used for treating diseases which respond to dopamine D3 receptor antagonists or dopamine D3 receptor agonists, eg. for treating diseases of the central nervous system, in particular schizophrenia, depressions, neuroses, psychoses, parkinson and anxiety.
Within the context of the present invention, the following expressions have the meanings given in conjunction with them: Alkyl (also in radicals such as alkoxy, alkylamino, etc.) is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms and, in particular, from 1 to 4 carbon atoms. The alkyl group can have one or more substituents which are selected, independently of each other, from OH, OC1-C6-alkyl, halogen or phenyl.
Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, etc.
Cycloalkyl is, in particular, C3-C6-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Alkylene radicals are straight-chain or branched. If A does not have any group Z, A then comprises from 4 to 10 carbon atoms, preferably from 4 to 8 carbon atoms. The chain between the triazole nucleus and group B then has at least 4 carbon atoms. If A has at least one of said Z groups, A then comprises from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms.
If the alkylene groups comprise at least one of the Z groups, these may either be arranged in the alkylene chain at an arbitrary site or in position 1 or 2 of group A (seen from the Ar1 radical). The radicals CONR2 and Coo are preferably arranged such that the carbonyl group is facing the triazole ring. Particularly preferred are compounds of the formula I in which A is xe2x80x94Zxe2x80x94C3-C6-alkylene, in particular xe2x80x94Zxe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94Zxe2x80x94CH2CH2CH2CH2xe2x80x94, xe2x80x94Zxe2x80x94CH2CH=CHCH2xe2x80x94, xe2x80x94Zxe2x80x94CH2C(CH3)=CHCH2xe2x80x94, xe2x80x94Zxe2x80x94CH2C(=CH2)CH2xe2x80x94, xe2x80x94Zxe2x80x94CH2CH(CH3)CH2xe2x80x94 or a linear xe2x80x94Zxe2x80x94C7-C10-alkylene radical, with Z being attached to the triazole ring. Z is preferably CH2, O and in particular S. Further preferably is A xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94CH2CH2CH=CHCH2xe2x80x94, xe2x80x94CH2CH2C(CH3)xe2x95x90CHCH2xe2x80x94, xe2x80x94CH2C(xe2x95x90CH2)CH2xe2x80x94, or xe2x80x94CH2CH2CH(CH3)CH2xe2x80x94.
Halogen is F, Cl, Br or I.
Haloalkyl can comprise one or more, in particular 1, 2, 3 or 4, halogen atoms which can be located on one or more C atoms, preferably in the xcex1- or xcfx89-position. CF3, CHF2, CF2Cl or CH2F are particularly preferred.
Acyl is preferably HCO or C1-C6-alkyl-CO, in particular acetyl. When Ar1 is substituted, the substituent can also be located on the nitrogen heteroatom.
Preferably, Ar1 is 
where
R3 to R6 are H or the abovementioned substituents of the radical Ar1,
R7 is H, C1-C6-alkyl or phenyl, and
X is N or CH. If the phenyl radical is substituted, the substituents are preferably in the m position or the p position.
Particularly preferably, Ar1 is 
where R3 and R4 have the abovementioned meanings. The phenyl, pyrazinyl and pyrrole radicals which are indicated are particularly preferred.
The radicals R3 to R6 are preferably H, C1-C6-alkyl, OR2, CN, phenyl which may be substituted by C1-C6-alkyl, C1-C6-alkoxy or halogen, CF3 and halogen and, in particular, H, C1-C6-alkyl, OR2 and halogen. In this context, R2 has the abovementioned meanings.
The radical B is preferably 
The radical Ar2 may have one, two, three or four substituents, preferably one or two substituents, which are located, in particular, in the m position and/or the p position. They are preferably selected, independently of each other, from C1-C6-alkyl, haloalkyl, NO2, halogen, in particular chlorine, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, cyclopentyl and cyclohexyl. When one of the substituents is C1-C6-alkyl, a branched group and, in particular, isopropyl or t-butyl is preferred.
Ar2 is preferably unsubstituted or substituted phenyl, 2-, 3- or 4-pyridinyl or 2-, 4(6)- or 5-pyrimidinyl.
When one of the substituents of the radical Ar2 is a 5- or 6-membered heterocyclic ring, the ring is then, for example, a pyrrolidine, piperidine, morpholine, pyridine, pyrimidine, triazine, pyrrole, thiophene, or pyrazole radical, with a pyrrole, pyrrolidine, pyrazole or thienyl radical being preferred.
When one of the substituents of the Ar2 radical is a carbocyclic radical, this latter radical is then, in particular, a phenyl, cyclopentyl or cyclohexyl radical.
When Ar2 is fused to a carbocyclic radical, this latter radical is, in particular, a naphthalene or dihydro- or tetrahydro-naphthalene radical.
According to an embodiment the invention relates to compounds of formula I, wherein Ar1 is a heterocyclic aromatic ring as defined above, B is 
and A and Ar2 have the meanings given above.
The invention also encompasses the acid addition salts of the compounds of the formula I with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Other useful acids are described in Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 ff., Birkhxc3xa4user Verlag, Basle and Stuttgart, 1966.
The compounds of formula I can have one or more centers of asymmetry. The invention therefore also includes the relevant enantiomers and diastereomers in addition to the racemates. The respective tautomeric forms are also included in the invention.
The process for preparing the compound (I) comprises
a) reacting a compound of the formula (II) 
where Y1 is a customary leaving group such as Hal, alkanesulfonyloxy, arylsulfonyloxy, etc., with a compound of the formula (III) 
or
b) reacting a compound of the formula (IV) 
where Z1 is O, NR2, or S and A1 is C1-C10-alkylene or a bond, with a compound of the formula (V) 
where Y1 has the abovementioned meaning and A2 is C2-C10-alkylene, where A1 and A2 together have from 3 to 10 C atoms and A1 and/or A2 optionally comprises at least one group Z; or
c) reacting a compound of the formula (VI) 
where Y1 and A1 have the abovementioned meanings, with a compound of the formula (VII) 
where Z1 has the abovementioned meanings; or
d) reversing the polarity of a compound of the formula (VIII) 
using reagents which are known from the literature, such as 1,3-propanedithiol, KCN/water, TMSCN or KCN/morpholine, as described, for example, in
Albright Tetrahedron, 1983, 39, 3207 or
D. Seebach Synthesis 1969, 17 and 1979, 19 or
H. Stetter Angew. Chem. Int. Ed. 1976, 15, 639 or
van Niel et al. Tetrahedron 1989, 45, 7643
Martin et al. Synthesis 1979, 633,
to give the products (VIIIa) (using 1,3-propanedithiol by way of example) 
and then chain-elongating with compounds of the formula (IX) 
where Y1 has the abovementioned meanings and A3 is C3-C9-alkylene, which may comprise a group Z
to give after deprotecting and reducing, compounds of the formula (Ia) 
where Z2 is CO, or a methylene group, and Z2 and A2 together have from 4 to 10 C atoms; or
e) reacting a compound of the formula (VIII) with a compound of the formula X 
where Y2 is a phosphorane or a phosphonic acid ester, by a method analogous to customary methods, as described, for example, in Houben weyl xe2x80x9cHandbuch der Organischen Chemiexe2x80x9d [Handbook of organic chemistry], 4th edition, Thieme Verlag Stuttgart, Volume 5/1b p. 383 ff. or Volume 5/1c p. 575 ff.
The process for preparing a compound of the formula I where A comprises the group COO or CONR2 comprises in reacting a compound of the formula (XI) 
where Y3 is OH, OC1-C4, Cl or, together with CO, is an activated carboxyl group, and A4 is C0-C9-alkylene, with a compound of the formula (XII) 
where Z3 is OH or NH2.
The compounds of the formula (III) are starting compounds for preparing compounds of the formulae (V), (VII) and (XII), and are prepared by standard methods as described, for example, in J. A. Kiristy et al., J. Med. Chem. 1978, 21, 1303 or C. B. Pollard, J. Am. Chem. Soc. 1934, 56, 2199 or by
a) reacting, in a known manner, a compound of the formula (XIII) 
where Q is H or a customary amine protecting group, with a compound of the formula (XIV) 
where Y4 is B(OH)2, xe2x80x94SnR3 (R3=butyl or phenyl), trifluoromethanesulfonyloxy, or has the meanings given for Y1, and R is C1-C4-alkyl; or
b) reacting a compound of the formula (XV) 
where B1 is 
where Q is H or a customary amino protecting group, eg. butyloxycarbonyl, benzyl or methyl, and Y4 is a leaving group, eg. OTf, SnBu3, B(OH)2 or halogen, with a compound of the formula (XIVa) 
where Y5 is a boron derivative, such as B(OH)2, or a metal-containing leaving group, for example SnR3 (R3=butyl or phenyl) or zinc halide, if Y4 is halogen or trifluoromethylsulfonyloxy, or Y5 is halogen or trifluoromethylsulfonyloxy, if Y4 is a boron derivative, such as B(OH)2, or a metal-containing leaving group, for example SnR3 or zinc halide, as described in
S. Buchwald et al. Angew. Chem. 1995, 107, 1456 or J. F. Hartwig et al. J. Am. Chem. Soc 1996, 118, 7217 or
S. Buchwald J. Org. Chem. 1997, 62, 1264 or F. Kerrigan et al., Tetrah. Lett. 1998, 39, 2219 and the literature cited in that document, or
J. K. Stille, Angew. Chem. 1986, 98, 504 or
J. K. Stille et al. J. Org. Chem. 1990, 55, 3014 or
M. Pereyre et al. xe2x80x9cTin in Organic Synthesisxe2x80x9d, Butterworth 1987; or
c) reacting a compound of the formula (XVI) 
where Q has the abovementioned meanings, with a compound Mxe2x80x94Ar2, where M is a metal such as Li, or MgY6, and y6 is Br, Cl or I. Mxe2x80x94Ar2 can be obtained from compounds of the formula (XIV) using methods which are known from the literature, or
d) preparing a compound of the formula (XVII) 
wherein B2 is 
and Q has the abovementioned meaning, by reduction, for example hydrogenations of compounds of the general formula Q-B3-Ar2 (IIIa), wherein B3 is one of the abovementioned unsaturated radicals B, using methods which are known from the literature.
Compounds of type B are either known or are obtained in a similar way to know methods as e.g. 1,4-diazacycloalkanes: L. Borjeson et al., Acta Chem. Scand. 1991, 45, 621; Majahrzahl et al. Acta. Pol. Pharm., 1975, 32, 145; 1-azacycloheptanones: A. Yokoo et al., Bull Chem. Soc. Jpn. 1956, 29, 631 and WO 97/25324.
In the above formulae, Ar1, R1, A, B, Z and Ar2 are as defined above.
Compounds of the Ar1-triazole, Ar2, Ar1 type are either known or can be prepared using known methods, as described, for example, in S. Kubota et al. Chem. Pharm. Bull 1975, 23, 955 or A. R. Katritzky, C. W. Rees(ed.) xe2x80x9cComprehensive Heterocyclic Chemistryxe2x80x9d, Pergamon Press, or xe2x80x9cThe Chemistry of Heterocyclic Compoundsxe2x80x9dxe2x80x99 J. WileyandSons Inc. NY and the literature cited in that document.
The compounds of the formula VIII are novel and are likewise part of the subject-matter of the present invention.
Compounds of the (VIII) and (XI) type, where A is C0-alkylene, can be prepared by metallating the 3-aryl-5-H-1,2,4(4H)-triazoles 
and by a method similar to methods described in T. Kauffman et al. Angew. Chem. Int. Ed. Engl. 1972, 11, 846 or by A. R. Katritzky, C. W. Rees(ed.) xe2x80x9cComprehensive Heterocyclic Chemistryxe2x80x9d, Pergamon Press Vol. 5, p 753.
The novel compounds and the starting materials and intermediates can also be prepared by a method similar to the methods described
The above-described reactions generally take place in a solvent at between room temperature and the boiling temperature of the solvent employed. Examples of solvents which can be used are esters, such as ethyl acetate, ethers, such as diethyl ether or tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethoxyethane, toluene, xylene, ketones, such as acetone or methyl ethyl ketone, or alcohols, such as ethanol or butanol.
If desired, the reaction can be carried out in the presence of an acid binder. Suitable acid binders are inorganic bases, such as sodium or potassium carbonate, sodium or potassium hydrogen carbonate, sodium ethoxide or sodium hydride, or organometallic compounds, such butyllithium, or alkylmagnesium compounds, or organic bases, such as triethylamine or pyridine. The latter can simultaneously serve as solvents.
The reactions may be carried out using a catalyst, such as transition metals and their complexes, eg. Pd(PPh3)4, Pd(OAc)2 or Pd(P(oTol)3)4, or using a phase transfer catalyst, eg. tetrabutylammonium chloride or tetrapropylammonium bromide.
The crude product is isolated in a customary manner, for example by filtering, by distilling off the solvent or by extracting from the reaction mixture, etc. The resulting compounds can be purified in a customary manner, for example by recrystallization from a solvent, by chromatography or by conversion into an acid addition compound.
The acid addition salts are prepared, in a customary manner, by mixing the free base with the appropriate acid, where appropriate in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl t-butyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.
When used for treating the abovementioned diseases, the novel compounds are administered orally or parenterally (subcutaneously, intravenously, intramuscularly, or intraperitoneally) in a customary manner. They can also be administered through the nose/throat region using vapors or sprays.
The dose depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active compound is from about 10 to 1000 mg per patient and day in the case of oral administration and from about 1 to 500 mg per patient and day in the case of parenteral administration.
The invention also relates to pharmaceuticals which comprise the novel compounds. These pharmaceuticals are present, in the customary pharmacological administration forms, in solid or liquid form, for example as tablets, film tablets, capsules, powders, granules, coated tablets, suppositories, solutions or sprays. In this context, the active compounds can be worked up together with the customary pharmacological auxiliary substances, such as tablet binders, fillers, preservatives, tablet disintegrants, flowance agents, emollients, wetting agents, dispersants, emulsifiers, solubilizers, retarding agents, antioxidants and/or propellant gases (cf. H. Sucker et al., Pharmazeutische Technologie [Pharmaceutical Technology], Thieme-Verlag, Stuttgart, 1978). The resulting administration forms normally comprise the active compound in a quantity of from 1 to 99% by weight.
The following examples serve to explain the invention without limiting it.